Plastic changes in cellular and subcellular mechanisms are critical determinants of neurobehavioral manifestations; of nervous system function. We propose to investigate the regulation of the septohipppocampal (S-H) system by nerve growth factor (NGF). The central hypothesis is that an intrahippocampal gain of NGF function in mice enhances activity of septal cholinergic neurons in the short term and, in the long term, leads to synantic reorganization in both the medical septum/nucleus of Diagonal Band (MS/nDB) and hippocampus and, thereby neurotransmission along the S-H system. To test this hypothesis, we will use as experimental model transgenic mice harboring a targeted intrahippocampal gain of NGF function. The experiments, incorporating patch clamp recording, immunohistochemistry and PCR-Amplified Detection of Immunoreactivity (PADI), are organized into three specific aims. Specific Aim 1 will test the hypothesis that GABAergic MS/nDB neurons are under regulation of a muscarinic tone that is maintained by cholinergic activity in the MS/nDNB. Specific Aim 2 will test the hypothesis that a targeted activation and increase in the expression of NGF in the hippocampus leads to changes in the properties of MS/nDNB neurons that are consistent with an augmented muscarinic tone and thus activity alongthe S-H pathway. Specific Aim 3 will employ a septohippocampal coculture system to test the hypothesis that the targeted activation of NGF is time- and activity-dependent. Inherent in testing these hypothesis is the notion that specific cellular and molecular changes can be correlated with NGF activation. Thus, in addition to the electrophysiological experiments, candidate proteins will be analyzed by a PCR-based protein detection technique in single neurons isolated by laser capture microdissection. Overall, this project will contribute to our understanding of the cellular and molecular bases underlying NGF-induced plasticity in the nervous system and explore the value of targeted gene transfer as a potential therapeutic strategy to ameliorate the debilitating consequences of cognitive dysfunction as seen in a variety of neurodegenerative conditions.